Infect Dis Clin N Am 16 (2002) 273295

Infective endocarditis in intravenous drug

abusers and HIV-1 infected patients
Jose M. Miro, MD, PhDa,c,*, Ana del Ro, MD, PhDa,
Carlos A. Mestres, MD, PhD, FETCSb,c
a

Infectious Diseases Service, Institut Clnic Infeccions i Immunologia, Institut dInvestigacions

Biome`diques August Pi i Sunyer-Hospital Clnic, Barcelona, Spain
b
Department of Cardiovascular Surgery, The Institute of Cardiovascular Diseases, Institut
dInvestigacions Biome`diques August Pi i Sunyer-Hospital Clnic, Barcelona, Spain
c
University of Barcelona, Barcelona, Spain

Infective endocarditis in IV drug abusers

Introduction
Parenteral drug addiction, particularly intravenous heroin abuse, presents an important challenge to health care programs worldwide. This
problem is most evident in developed countries, involving about 1.2 million
people in the United States (USA), 750,000 in European Economic Community (EEC) countries, and 100,000 in Australia [1]. Most of parenteral drug
addicts (PDAs) are young adults (20 to 35 years of age) and the male:female
case ratio is 3:1 [26].
Overall, the most common form of parenteral drug abuse is intravenous
or subcutaneous injection of heroin (mainliners and skin poppers)
[2,4,6]. The use of cocaine alone or cocaine combined with heroin in IV
injection (speedball) has been increasing in recent years [19,39,98]. Less
common choices include morphine, pentazocine, amphetamines, or benzodiazepines. In some instances a particular drug predominates in a local area,
for example pentazocine and tripelennamine (Ts and blues) in Detroit and
Chicago [710].
Parenteral drug addiction is associated with a wide range of medical complications. Infectious complications are the most common, being responsible
for 60% to 80% of hospital admissions and for 20% to 30% of deaths [1118].

* Corresponding author. Infectious Diseases Service, Hospital Clnic i Provincial, Villarroel

170, 08036 Barcelona, Spain.
E-mail address: miro@medicina.ub.es (J.M. Miro).
0891-5520/02/$ - see front matter
2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 1 ) 0 0 0 0 8 - 3

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Infective endocarditis (IE) is one of the most severe complications of IV

drug abuse [26,1315]. Early cases were reported in the United States in the
1930s [2]. Currently IV drug addiction is one of the most prevalent causes of
IE in urban medical centers in developed countries [15,19]. The incidence
among intravenous drug abusers (IVDAs) in the United States ranges
between 1% to 5% per year [4,14,15,20], with parenteral cocaine addicts having the highest risk [21]. IE in IVDAs is responsible for 5% to 20% of hospital admissions and for 5% to 10% of total deaths. IVDAs often have
recurrent endocarditis [2,4,14,15]. The incidence of IE in IVDAs in the
AIDS era is decreasing, probably due to changes in injection practices (such
as less use of the parenteral route of administration, increased use of sterile
needles and syringes, and less sharing of the injection paraphernalia) undertaken in order to avoid HIV transmission [15,22,23].
Etiology
Staphylococcus aureus is the etiological agent in most of the cases (60% to
70%) (see Table 1) [26,1215,24]. It predominates in the majority of geographic areas and is usually sensitive to methicillin (MSSA). In order of frequency, the next leading etiologic organisms are streptococci (viridans
streptococci, group A streptococcus), enterococci (15% to 20%), Pseudomonas aeruginosa, Serratia marcescens and other gram-negative rods (<10%),
and Candida sp (<2%) [26,1215,24]. Less common or rare etiologic organisms include Pseudomonas spp, Xanthomonas maltophilia, Neisseria spp,
Clostridium sp, Bacillus spp, Corynebacterium spp, coagulase-negative staphylococci (CNS), Erysiplothrix sp, Gemella morbillorum, Citrobacter spp,
Haemophilus spp, and Eikenella corrodens [25]. Endocarditis with polymicrobial infection is not rare, being reported in about 5% of cases and usually
Table 1
Etiology of infective endocarditis in IV drug abusers: analysis of 1529 episodes diagnosed in
Spain (19771993) [5,13]
Organisms

Episodes (%)

Staphylococcus aureus
Coagulase-negative
staphylococci
Viridans streptococci
Enterococci
Other streptococci
Pseudomonas aeruginosa
Other gram-negative
aerobes
Other organisms
Candida spp
Polymicrobial
Negative blood culture
endocarditis

1138 (74)
44 (3)
94
21
37
12
11

(6)
(1.5)
(2)
(<1)
(<1)

4
18
44
106

(<1)
(1.5)
(3)
(7)

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275

caused by P. aeruginosa, S. aureus, Haemophilus, or Candida [4,12,14,15].

Endocarditis with negative blood cultures occurs in 5% to 10% of cases
[26,1215,24]. All these percentages, however, can vary somewhat depending on the site aected in the heart [26,1215,24]. Furthermore, some regional and temporal etiological variations have been observed in the United
States [710,2629] and Europe [30].
IVDAs are subject to many needle-borne infectious diseases, including
bacterial infections introduced by self-inoculation [2,4,6,12,31,32]. Injection
of heroin, cocaine, and other drugs of abuse is a major risk factor for S. aureus bacteremia. S. aureus probably originates from the drug users own skin
[15,3336], while other bacteria and fungi may be found in the drugs themselves, adulterants, or contamination of the injection equipment or the diluents (tap water, lemon juice, or saliva) [33,37,38]. P. aeruginosa remains
viable in the drug combination of pentazocine and tripelennamine (Ts &
blues), thus explaining the increased incidence of P. aeruginosa infections
where this drug is consumed [7,10]. The lemon juice used to dissolve brown
heroin, contaminated by Candida albicans from the drug addicts oropharynx, is the source of infection in some cases of systemic candidiasis [11,39].
Finally, IVDAs can acquire several viral diseases (HIV-1, hepatitis B or C
virus) [2,4,12] and, potentially, infections with any microorganism circulating in their blood [31,32] as result of sharing injection equipment (syringes)
that may be contaminated by the blood of other infected IVDAs. This is
why IVDAs are usually HIV or HCV co-infected.
Valve involvement
The tricuspid valve is the most frequently aected, in about 70% of cases,
followed by the mitral and aortic valves in 20% to 30%, while pulmonic
valve infection is rare (<1%) (see Table 2) [26,1215,24,40]. Both left- and
right-sided valves are involved simultaneously (mixed IE) in 5% to 10% of
Table 2
Valve involved in 1529 episodes on infective endocarditis in Spanish IV drug abusers (1977
1993) [5,13]
Aected side and valve

Cases (%)

Right-sided endocarditis
Tricuspid valve
Pulmonic valve
Tricuspid and pulmonic valves
Unknown
Left-sided endocarditis
Aortic valve
Mitral valve
Aortic and mitral valves
Mural/Coarctation of aorta
Unknown
Mixed (right and left) endocarditis

1199
1045
14
8
132
254
103
98
27
3
24
76

(79)
(68)
(1)
(<1)
(9)
(16)
(7)
(6)
(1.5)
(<1)
(1.5)
(5)

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cases. Only 10% to 30% of IVDAs have underlying cardiac pathology,

mainly involving the mitral and aortic valves [26,1215,24,40].
The reason for the predominance of tricuspid valve involvement in
IVDAs is unknown. One hypothesis is that endothelial damage is caused
by physical bombardment of the tricuspid valve by impurities contained
in injected drugs or adulterants [41]. Several pathological studies of tricuspid
valves from IVDAs who died of unrelated causes showed no such endothelial damage, however [15]. Attempts to reproduce tricuspid valve endocarditis in a rabbit model by injecting street heroin over several weeks followed
by intravenous challenge with a high inoculum of S. aureus inocula were
unsuccessful [15,42]. In a recent review, Frontera and Gradon [43] analyzed
other theories. Proposed hypotheses include: cocaine-induced micro-thrombi
on cardiac valves, drug-induced pulmonary hypertension with increased
right-sided intracardiac turbulence, increased right-sided expression of
matrix molecules capable of binding microorganisms in IVDA, the etiological microorganism itself, and HIV infection [43]. However, the authors concluded that no single hypothesis can explain the frequency of tricuspid valve
infection; some combination of the above is probably responsible [43].
Diagnosis
Clinical suspicion
IE in IVDAs usually causes an acute febrile syndrome with variable
symptoms and signs, according to the organism and the site involved
(Tables 4 and 5) [26,1215,24,40].
Drug addicts with right-sided IE present with cough, pleuritic chest pain,
and sometimes hemoptysis and dyspnea [26,12,14,15,24,42]. Peripheral vascular phenomena are rarely present. On admission, the murmur of tricuspid
insuciency is usually absent, but appears later in about half of patients [2
6,12,14,15,24,42]. Right heart failure is an uncommon complication. Chest
radiograph lms reveal single or multiple rounded or segmented pulmonary
inltrates. These may be cavitated or become associated with pleural eusions
or empyema in up to 75% of cases (see Fig. 1) [26,12,14,15,24,42]. Pneumothorax is an unusual complication [44]. The etiological agent is most often
S. aureus (80% to 90%) or P. aeruginosa (5% to 10%) [26,1215,24,42].
Clinical features of IVDAs with left-sided IE are similar to those of endocarditis on native valves in the non-drug addict population [2,4,6,12,14,
15,24,42]. Murmurs, underlying heart disease, left heart failure, systemic
emboli, and peripheral valvular phenomena are frequently present [2,4,6,
12,14,15,24,42]. Although S. aureus remains the most common etiological
agent (25% to 35%), a signicant number of cases are caused by viridans
streptococci and enterococci (25%), gram-negative bacilli (P. aeruginosa and
S. marcescens; 10%), and Candida sp (5% to 10%) [26,1215,24,42].
Finally, it is important to keep in mind that the rst clinical manifestations of S. aureus endocarditis may be due to septic metastases to the

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277

Fig. 1. Chest radiograph of a female IV heroin addict with S. aureus tricuspid endocarditis
showing bilateral inltrates secondary to septic pulmonary embolizations.

meninges, brain, joints, bones, spleen, or other sites. These may confuse the
diagnostic process, and when present they are associated with a worse prognosis [2,46,12,14,15,24,42]. Sometimes disseminated intravascular coagulation (DIC) may develop. The associated petechial and purpuric skin lesions
may lead to a misdiagnosis of meningococcemia if the patient has signs of
meningitis [15].
Diagnostic criteria
Diagnosis of IE is made according to the clinical, microbiological, and
echocardiographical criteria described by Durack et al. [45]. It is also important to take into account that the clinical hallmark of right-sided endocarditis is the presence of radiological pulmonary inltrates, and that in IVDAs
one must discard peripheral septic thrombophlebitis [2,4,6,12,14,15,24,
42,46]. If the patient has HIV infection, it is important not to confuse
right-sided IE with a community-acquired pneumonia or P. carinii pneumonia. Bidimensional echocardiography and blood cultures are the most eective diagnostic tools for diagnosing IE in IVDAs [2,4,6,12,14,15,24,42].
Transthoracic echocardiography (TTE) remains useful for detecting vegetations and identifying the aected valve (see Fig. 2) [4648]. In right-sided
endocarditis, TTE detects tricuspid vegetations with a reported sensitivity
as high as 80% [42,46,4951], a sensitivity similar to that of transesophageal
echocardiography (TEE) [52]. Blood cultures are positive in 80% to 100% of
cases [6,12,14,15,24,40,42].

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Fig. 2. Transthoracic echocardiography of a male IV heroin addict with S. aureus right side
endocarditis showing a large tricuspid valve vegetation (arrowhead). Top: during diastolic
period; bottom: during systolic period. VD right ventricle; AD right atrium. (Courtesy of
M. Azqueta, MD, Barcelona, Spain).

Prognosis
In the past two decades endocarditis has become one of the most prevalent causes of death in patients with drug addiction. In several recent studies,
mortality ranged between 5% and 30% [26,1215,24,42]. Mortality depends
on the side of the heart involved and the etiological agent [2,4,6,1215]
(Table 3). The prognosis of right-sided staphylococcal endocarditis is usually good (mortality <5%, with surgery <2%) [26,1215,24,42]. Patients with
tricuspid valve vegetations >2 cm in size [50] and with ARDS [53] have high
mortality (P < 0.05). The prognosis of left-sided IE, particularly when the
aortic valve is involved, is notably worse (mortality 20% to 30%, with
surgery 15% to 25%) [19,37,39,48,54,6264,80,93,98]. IE caused by gramnegative bacilli or fungi has the worst prognosis. Heart failure and systemic embolization (especially to the CNS) are the main causes of mortality
[26,1215,24,42].

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279

Table 3
Surgery and mortality of 1106 episodes of methicillin-susceptible Staphylococcus aureus
(MSSA) endocarditis in Spanish IV drug abusers (197793) according to the side of the heart
involved [13]

Surgery
Mortality
a

Right-sided IE
N 950

Left-sided IEa
N 156

OR (95% CI)

P value

1%
5%

15%
28%

18 (843)
7 (411)

<0.001
<0.001

55 episodes of mixed (right + left) MSSA endocarditis were included in this group.

Antibiotic treatment
The authors will focus on the antibiotic treatment of right-sided endocarditis because it is especially important in IVDAs. The duration of therapy
for right-sided infections can be shortened in some cases. Favorable factors
are that the density of bacteria in right-sided vegetations is smaller than on
the left side [24,5456], and prognosis of right-sided endocarditis is very
good [26,1215,24,42].
Antibiotic therapy for left-sided endocarditis in IVDAs is essentially the
same as in the general population with native or prosthetic valve endocarditis.
Empiric therapy
The choice of empiric therapy at admission depends primarily on the suspected microorganism, side of the heart involved, and type of drug injected,
as summarized in Table 4 [26,1215,24,42]. Because S. aureus is the most
common microorganism on both sides of the heart, it must always be
covered [26,1215,24,42]. In this case the treatment will include antistaphylococcal antibiotics (nafcillin, cloxacillin, or vancomycin, depending
on the methicillin-resistant S. aureus [MRSA] prevalence [8,9,30] in the geographical area aected). If IVDAs are addicted to pentazocine [7,10] an antipseudomonas antibiotic therapy should be added to the previous treatment;
if IVDAs use brown heroin dissolved with lemon juice [11,39], candidemia
should be considered and an antifungal treatment (e.g., uconazole) may
be added. On the other hand, in IVDAs with underlying valvulopathy or
left-sided involvement, antibiotics eective against streptococcus and enterococcus must be included [26,1215,24,42] until blood culture results
become available.
Once the causative agent has been isolated, therapy must be adjusted to
its antibiotic susceptibility pattern [5761].
Therapy of methicillin-susceptible S. aureus endocarditis
The standard therapy for methicillin-susceptible S. aureus (MSSA) endocarditis on the native valve is a 4 to 6 week course of nafcillin or cloxacillin
(8 g/day to 12 g/day) [2,4,6,1215,5759,61]. An aminoglycoside (usually
gentamicin) can be given during the rst 3 to 5 days of therapy to reduce the
duration of fever, leukocytosis, and bacteremia [6,12,15,57,59,61]. If the

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Table 4
Empiric antimicrobial therapy for infective endocarditis in IV drug abusers
Side of the heart involved

Most probable organisms

Initial antibiotic therapy

Right/mixed

Common: S. aureusa
Less common:
P. aeruginosab,
estreptococci, Candidac,
other bacteria

Penicillinase-resistant
penicillind plus gentamicin

Left

Common: S. aureusa,
estreptococci, enterococci
Less common:
P. aeruginosab,
other GNR,
Candidac, other bacteria

Ampicillin plus
penicillinase-resistant
penicillind plus
gentamicin

a
If methicillin-resistant S. aureus (MRSA) predominates in a given country, vancomycin
replaces penicillinase-resistant penicillin.
b
If IVDA uses pentazocine, add an anti-pseudomonas agent to the previous regimens to
cover P. aeruginosa infection.
c
If IVDA uses brown heroin dissolved with lemon juice, add an antifungal agent to the
previous regimens to cover C. albicans infection.
d
Nafcillin or cloxacillin.

patient is allergic to penicillin the antibiotic treatment of choice will be a

rst-generation cephalosporin (cefazolin 2 g/8 h IV) for patients without
anaphylactic reactions and vancomycin or teicoplanin for patients with anaphylactic reactions (see Table 5) [6,12,14,15,5759]. If S. aureus is susceptible
to penicillin G (<5%), this antibiotic (12 million units/day to 18 million units/
day IV) should be given instead of nafcillin or cloxacillin for the same period
of time [5759,61].
Rationale for a two-week course of combination therapy for MSSA right-sided
endocarditis in IVDAs. Short-duration treatment (two weeks) is an option
for selected cases of right-sided endocarditis [62,63]. This is possible because
right-sided endocarditis due to MSSA has a very good prognosis [26,12
15,24,42,64]. While patients with left-sided endocarditis have surgery and
mortality ratios ranging 15% to 20% and 25% to 30%, respectively, the incidence of these complications is low in the right side of the heart (less than
2% and 5%, respectively) [26,1215,24,42,64]. The reasons for the good
prognosis of right-sided S. aureus endocarditis are not clear, but may be
explained by observations made in the experimental endocarditis model
30 years ago by Freedman and colleagues [6567]. They noted that the natural course of right-sided staphylococcal endocarditis was dierent from
that of left-sided endocarditis. In their study, all but one rabbit with aortic
endocarditis died before 2 weeks while most rabbits with tricuspid endocarditis were alive after 2 weeks of infection. Furthermore, if after the infection
the catheter was removed from the rabbits [67], the percentage of animals

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281

Table 5
Recommended antibiotic regimens for methicillin-susceptible S. aureus endocarditis in IVDAs
Type of endocarditis
Non-complicated right-sided IEa

Non-complicated left-sided IE

Complicated native valve IEc

Prosthetic valve IE

Recommended antibiotics
(dosage, route, and duration)
Nafcillin or cloxacillinb 2 g/4h IV for 2
weeks + gentamicin 1 mg/kg/8h IV/IM rst
5 days, or Ciprooxacin 750 mg/12h
po + rifampin 300 mg/12h po for 4 weeks
Nafcillin or cloxacillinb 2 g/4h IV for 4
weeks + gentamicin 1 mg/kg/8h IV/IM rst
5 days
Nafcillin or cloxacillinb 2 g/4h IV for 6
weeks + gentamicin 1 mg/kg/8h IV/IM rst
5 days
Nafcillin or cloxacillinb 2 g/4h IV + rifampin
300 mg/8h po for 6 weeks + gentamicin
1 mg/kg/8h IV/IM for 2 weeks

a
The short-course treatment is only recommended for uncomplicated cases (see text for the
exclusion criteria).
b
If the patient is allergic to penicillin the eligible antibiotic treatment will be a
cephalosporin (cefazolin 2 g/8h IV) for patients without anaphylactic reactions and vancomycin
(1 g/12h IV) or teicoplanin (610 mg/kg/12h for 9 doses and thereafter 610 mg/kg/24h IV or
IM) for patients with anaphylactic reactions.
c
It is recommended to prolong therapy until 6 weeks for complicated cases: left heart
failure, renal failure, local or systemic septic metastases, vegetation size >2 cm in diameter, and
prosthetic valve endocarditis.

with spontaneous sterilization of the valve vegetations was greater in the

right side of the heart, with the density of bacteria of the infected tricuspid
valve vegetations being smaller as well. Finally, Sande et al. [68,69] demonstrated in the 1970s that for susceptible S. aureus endocarditis, the time
required to sterilize vegetations with penicillin or nafcillin plus an aminoglycoside was approximately one half the time of penicillin or nafcillin alone.
The good prognosis of right-sided S. aureus endocarditis and these experimental data provide the rationale for testing short-course therapy for
right-sided endocarditis caused by MSSA.
In 1998 Chambers et al. [70] published the rst study showing the ecacy
of a 2-week course of nafcillin plus tobramycin for the therapy of right-sided
MSSA endocarditis in IVDAs. 94% of the 50 patients treated were cured
with this regimen. Table 6 summarizes the studies published between 1988
and 2001 [7075] with a 2-week course of nafcillin or cloxacillin plus an aminoglycoside (usually gentamicin) for the therapy of non-complicated rightsided MSSA endocarditis in IVDAs. Overall, 209 cases have been treated,
with an overall cure rate of greater than 90%. There were seven failures during the treatment, including ve relapses; only three patients died.
What is the role of aminoglycosides for the treatment of right-sided
MSSA endocarditis? In a classic clinical trial published almost 20 years ago,
Korzeniowski et al. [76] demonstrated that the addition of gentamicin for

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J.M. Miro et al / Infect Dis Clin N Am 16 (2002) 273295

Table 6
Published studies with nafcillin or cloxacillin plus an aminoglycoside for 2 weeks for right-sided
methicillin-sensitive S. aureus endocarditis in IV drug abusers (IVDAs) [42,7075]
Author (year)

Tx

Chambers (1988)
Espinosa (1993)
Torres-Tortosa (1994)
Miro (1994)
Fortun (1995)
Ribera (1997)
Fortun (2001)

Naf+Tob
Clo+Gen
Clo+Amk
Clo+Gen
Clo+Gen
Clo+Gen
Clo+Gen

Total

N
50
12
72
20
8
36
11
209

Cures
47
12
67
19
7
31
11
194 (93%)

Failures/relapses

Deaths

0/3
0/0
4/0
0/1
1/0
2/1
0/0

0
0
1
0
0
2
0

7/5 12 (6%)

3 (1%)

Tx Antibiotic therapy; Naf nafcillin (IV 1.5 g/4h); Tob tobramycin (IV 1 mg/kg/8h);
Clo cloxacillin (IV 2 g/4h); Gen gentamicin (IV 1 mg/kg/8h); Amk amikacin (7.5 mg/kg/
12h).

the rst 2 weeks of a 4- to 6-week course of nafcillin failed to improve cure

rates of staphylococcal endocarditis in IVDAs and non-IV drug abusers.
Because the combination was associated with a more rapid clearing of bacteremia, however, the American Hospital Association (AHA) recommended the
addition of gentamicin for the rst 3 to 5 days [57,59]. In a descriptive study,
Miro et al. [77] had the opportunity to follow ten IVDAs with right-sided
S. aureus endocarditis who left the hospital against medical advice before nishing the 4 weeks treatment, having received 10 to 14 days of cloxacillin but
only one week of gentamicin. All patients were cured without relapses or
deaths after a follow-up period ranging between 3 and 18 months. Ribera
et al. [74] have recently demonstrated that two weeks of monotherapy with
cloxacillin is as eective as the combination therapy with cloxacillin plus gentamicin for treating right-sided MSSA IE. The cure rate for the arm of cloxacillin alone was almost 90%. These data suggest that the addition of an
aminoglycoside is not essential for right-sided MSSA endocarditis. However,
its addition for the rst 3 to 5 days of therapy may have some therapeutic
value due to its synergistic eect with penicillinase-resistant penicillins [57].
Exclusion criteria for two-week course of combination therapy for MSSA
right-sided endocarditis in IVDAs. The standard 4-week regimen must be
used in these situations:
1. Slow clinical or microbiological response (>96 hours) to the initial antibiotic therapy [57,62,63];
2. Complicated right-sided endocarditis; presence of right heart failure,
valve vegetations >2 cm in diameter, acute respiratory failure, empyema, septic metastatic foci outside the lungs, or extracardiac complications (e.g., renal failure) [49,50,57,62];
3. Therapy with antibiotics other than penicillinase-resistant penicillins
(e.g., rst-generation cephalosporins, glycopeptides) (see Other treat-

J.M. Miro et al / Infect Dis Clin N Am 16 (2002) 273295

283

ments for right-sided MSSA endocarditis in IVDAs section) [63,70,72,

73,78];
4. Right-sided endocarditis caused by MRSA or polymicrobial infections;
5. IVDA with severe immunosupression (<200 CD4 cells/lL) or AIDS (see
Inuence of HIV-1 infection in endocarditis in IVDAs section).
Other treatments for right-sided MSSA endocarditis in IVDAs. Right-sided
S. aureus endocarditis in IVDAs can be treated successfully with ciprooxacin plus rifampin given by oral route [79,80]. Heldman and colleagues [80]
demonstrated that oral antibiotic treatment with ciprooxacin plus rifampin
for 4 weeks was as eective as the recommended 4-week regimen with oxacillin plus gentamicin. This oral regimen may be a reasonable alternative to
parenteral therapy in some patients. It should be taken into account, however, that resistance to one or both drugs during the treatment has been
described [81].
It is important to remember that people who are addicted to drugs with
MSSA right-sided IE treated with vancomycin or teicoplanin combined with
an aminoglycoside for 2 weeks [70,73] or given alone for 4 weeks [72,78]
have an unacceptable failure rate. This is the same for left-side involvement
and MRSA infections [67,82]. There are several explanations for glycopeptide treatment failure of MSSA endocarditis in IVDAs: (1) glycopeptides are
less rapidly bactericidal against MSSA compared to penicillinase-resistant
penicillins [78], (2) glycopeptides have poor diusion into valve vegetations
(e.g., teicoplalnin has a peripheral pattern) [83], and (3) the renal clearance of
glycopeptides in IVDAs is greater than in healthy volunteers [84,85]. For
this reason, IVDAs with IE treated with these drugs should be monitored
closely to check the eectiveness of the treatment. Therefore, vancomycin
or teicoplanin should be used only in patients with allergy to penicillin and
should be given for at least 4 weeks; plasma serum levels should be monitored often, and gentamicin should be added during the rst 1 to 2 weeks
of therapy.
Therapy of other etiological agents
Antibiotic therapy for endocarditis caused by MRSA, viridans group
streptococci, S. bovis, enterococci, and HACEK group is the same as in the
non-addict population [54,5761]. Antibiotic therapy for other gram-negative rodsespecially S. marcescens and P. aeruginosashould be started
according to general recommendations, taking into account that surgical
therapy will likely be required [12,15,86]. In cases of right-sided P. aeruginosa
endocarditis the initial therapy may be more conservative because cure can
often be achieved without surgery. This is possible because, as in right-sided
S. aureus endocarditis, the density of P. aeruginosa in the vegetations of tricuspid valve endocarditis is smaller than in aortic or mitral endocarditis
[8,9,64,86]. For this reason, tricuspid surgery should be done only in cases

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J.M. Miro et al / Infect Dis Clin N Am 16 (2002) 273295

of persistent or recurrent P. aeruginosa bacteremia despite optimal antimicrobial therapy for at least 7 days (see Surgical therapy section). The
therapy of choice is administration of ceftazidime, meropenem/imipenem,
piperacillin, or ciprooxacin plus high doses of an aminoglysoside (e.g., tobramycin or amikacin) for at least 6 weeks. Therapy for fungal endocarditis
should also be started according to the general recommendations [12,15] prior
to valve replacement (see Surgical therapy section).
Therapy of negative blood culture endocarditis
In these cases, initial antibiotic therapy should be given during the recommended period of time if there is a good clinical response (see Table 4). In
other clinical situations the approach will be the same as in the non-addict
population, taking into account that HIV-infected IVDAs can have a wide
dierential diagnosis because of AIDSrelated diseases.
Surgical therapy
The authors will discuss only the surgery of right-sided endocarditis with
tricuspid valve involvement. The indications for surgery and the technical
options for left-sided involvement are the same as in the general population
with native or prosthetic valve endocarditis [87,88]. Furthermore, two special
issues are usually taken into account before considering surgery in this population: the likelihood of continuing IV drug abuse with continuing risk of
reinfection, overdose, and other complications, and the issue of HIV infection (see Inuence of HIV-1 infection in endocarditis in IVDAs section).
This explains why the surgical approach is usually more conservative in IV
drug abusers; they have a higher incidence of recurrent IE compared to the
general population with IE [2,4,6,12,14,15], most often due to continued use
of IV drugs. Indeed, this type of surgery also requires special considerations
for IVDAs to avoid the development of prosthetic valve endocarditis if there
is continued use of IV drugs. Despite this, IV drug abuse by itself must not be
a contraindication for surgery. Several studies have shown that cardiac surgery improves the outlook for early and late survival of IVDAs with IE in
whom surgery is indicated. Mathew et al. [55] studied a cohort of 80 IVDAs
who underwent several types of operations for IE. The probability of survival
at 3 and 5 years was 74% and 70%, respectively, and these gures are comparable to the general population who underwent surgery for IE. Arbulu et al.
[89] found a survival rate of 64% at 22 years in a cohort of 54 IVDAs who
underwent surgery for right-sided IE.
Indications for right-sided surgery
There are two main indications for surgery in this type of endocarditis:
(1) endocarditis caused by microorganisms dicult to eradicate, such as fungal
etiology or persistent or recurrent bacteremia despite optimal antimicrobial
therapy for more than 7 days (e.g., S. aureus or P. aeruginosa endocarditis)

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285

[12,87,88], and (2) patients with tricuspid valve vegetations >2 cm with
dilated right ventricle (TTE) and recurrent pulmonary emboli or right heart
failure [49,50,53].
Technical options for right-sided involvement
In tricuspid valve endocarditis the surgical approach is very conservative.
Most surgeons opt to avoid the implantation of foreign material. The
options are: (1) total or partial valve resection without valve replacement
(tricuspid valvulectomy). This procedure helps prevent recurrent endocarditis if patients continue IV drug use [15,89,90]. This simple operation
described by Arbulu et al. almost 30 years ago [91,92] is usually indicated
as a life-saving maneuver. Long-term follow-up showed, however, that
10% to 15% of cases may require late implantation of a valve prosthesis
as a consequence of right-sided heart failure due to chronic massive tricuspid regurgitation [89,93,94]. (2) Vegetectomy or tricuspid valve repair [90].
This surgical approach should be used in all cases if possible. (3) Tricuspid
valve replacement with a biological or mechanical prosthesis. If this option
is deemed necessary, anticoagulation is recommended when mechanical
prosthesis are implanted. Fatal complications have been described in noncompliant IVDAs [89,94], and if IV drug abuse persists patients can develop
prosthetic endocarditis; in this case the prognosis is very poor [89,94]. Finally, (4) tricuspid valve replacement with a mitral homograft. This is a new
approach that has been performed successfully in some cases to avoid the
use of any synthetic material by transplanting a cryopreserved mitral homograft into the tricuspid position [95]. It was described by Pomar and Mestres
in 1993 [95]. Technically it is not a complex operation and provides valvular
competence in the acute phase, avoiding the appearance of late clinical right
heart failure [56,96,97]. Furthermore, if IV drug abuse persists, recurrent
endocarditis on the homograft can be managed conservatively without
operation [56,96,97]. A tricuspid homograft could also be used; however, tricuspid valves are seldom harvested as the tricuspid valve usually has fragile
tissues.
In the very unusual case of pulmonary valve endocarditis, the surgical
approach also has the same considerations. Pulmonary valvulectomy or the
replacement of the pulmonary valve with a pulmonary homograft are
the best surgical options [88].

Inuence of HIV-1 infection in endocarditis in IVDAs

Currently, the prevalence of HIV-1 infection among IVDAs with IE
ranges between 40% and 90% [40,73,74,80,98101]. The full consequences
of HIV infection in IE in IVDAs are not yet fully known because only a few
studies have been published on this topic [98103]. The main conclusions
from the literature review are the following.

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Incidence
Several epidemiological studies [20,104,105] have shown that HIV infection is associated with a several-fold increased risk of endocarditis in
IVDAs. Mano et al. [104] have shown that compared to HIV-negative
IVDAs, HIV-infected IVDAs with CD4 cell counts 350 cells/lL had an
OR of 2.31 (0.61 to 8.8) for developing IE, whereas those with a CD4 cell
count <350 cells/lL had an OR of 8.31 (1.2 to 56) for developing IE. However, the risk in HIV-infected patients who do not abuse drugs is not
increased (see Infective endocarditis in HIV-infected patients not related
to IV drug abuse section). HTLV-II infection has no inuence on the risk
of IE [106].
Clinical characteristics and etiology
HIV infection does not alter the febrile response of IVDA patients with
IE [107]. HIV-infected patients have lower WBC counts [99101] a higher
ratio of right-sided endocarditis and S. aureus infections than HIV-negative
IVDA patients [99,100].
Antibiotic therapy
Response to antibiotic therapy is similar among HIV-infected or nonHIV-infected IVDAs [74,80]. It is not known, however, if right-sided MSSA
endocarditis can be treated successfully with short-course therapy in HIVinfected IVDAs. Ribera et al. [74] and Fortun et al. [73] showed that
cure rates for asymptomatic HIV-infected IVDAs were the same as for
HIV-negative IVDAs (90% and 100%, respectively). In both studies, HIVinfected IVDAs had a mean/median CD4 cell count of
300/lL [73,74].
Although these data are very promising, the reality is that there is not
enough information about the ecacy of this short-course regimen in AIDS
or severely immunosupressed patients (CD4 cell counts <200/lL), the subgroups of HIV-infected patients with the highest mortality rates [98100].
It seems prudent, therefore, to treat these patients with the more active antibiotic regimens for 4 weeks.
Surgery
Cardiac surgery in HIV-infected IVDAs with IE does not worsen neither
the endocarditis nor the HIV infection prognosis [102,103].
Prognosis
Overall mortality between HIV-infected or non-HIV-infected IVDAs
with IE is similar [98100]. In HIV-infected IVDAs with endocarditis, however, several studies have demonstrated that the AIDS stage and severe

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287

immunosupression (CD4 cell counts <200/lL) worsened the prognosis of

endocarditis [98100].
Finally, opportunistic infections related to AIDS should also be considered in HIV-1-infected IVDAs with endocarditis because drug addicts may
have multiple simultaneous infections and the work-up may be dicult in
these circumstances.

Infective endocarditis in HIV-infected patients

not related to IV drug abuse
IE in HIV infection occurs almost exclusively in IVDAs; it is very rare in
other HIV-infected patients despite the fact that the number of HIV-infected
patients is increasing worldwide [108111]. Some case reports have been
published [25,112123]. Table 7 summarizes the main characteristics of 22
cases of endocarditis in HIV-1-infected patients not related to IV drug abuse
[108]. Eight cases were diagnosed in the authors institution between 1979
and 1999 and the remaining cases were found in a review of the literature
[25,112123].
Incidence
The incidence of IE in HIV-infected patients was 2% in a retrospective
database study from three sites in three countries (France, Spain, and the
United States) that included 647 non-IVDA patients with denite IE and
documented HIV status [109]. Eight of these cases were diagnosed in the
authors institution [86]. This represents 0.3% of all HIV-1infected nonIVDA patients and 2% of all IE in non-IVDAs [108]. Thus, as opposed to
HIV-infected IVDAs, HIV-1 infection by itself is not a signicant risk factor
for the development of IE despite the immune impairment that it causes.
Clinical characteristics and etiology
Ninety-ve percent of patients were men, and the mean age was 46 years
(range 24 to 64 years). The prevalence of men can be attributed to the predominance of homosexuality (45%) and hemophilia (14%) as HIV-1 risk factors. In more than half of the cases IE developed in patients with advanced
HIV-1 disease. Median (range) CD4 cell counts were 31/lL (4 cells/lL to
922 cells/lL). IE involved a native valve in 86% of episodes; 9% involved
a prosthetic valve. IE was community-acquired in only 59% of cases, the
incidence of nosocomial IE (41%) being higher than the general population
with IE. An underlying valve disease was found in 23% of cases. Aected
valves were usually the mitral (59%) or the aortic (45%) valves. The presence
of echocardiographical vegetations was similar to the general population
with IE [86]. Salmonella spp (23%) and Enterococcus faecalis (18%) were the
most frequently isolated microorganisms. Other etiological agents were

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Table 7
Characteristics of 22 episodes of infective endocarditis in HIV-1 infected patients not related to
active or former IV drug abuse (19801999) [25,108,112123]
Variables
Sex
Male
Female
HIV risk factor
Homosexuality
Heterosexuality
Blood product recipient
Unknown (no-IVDA)
HIV stage
A
C
no data
CD4/lL
<200
200
No data
Etiological agent
Enterococcus faecalis
Viridans group streptococci
Staphylococci
Streptococcus pneumoniae
Salmonella spp
Fungi
Other
Acquisition
Community
Nosocomial
No data
Type of valve
Native
Prosthetic
No data
Valve involved
Mitral
Aortic
Aortic and mitral
Tricuspid
No data
Surgery
Yes
No
No data
Mortality
Yes
No
No data

Number
of cases (%)
21 (95)
1 (5)
10
6
3
3

(45)
(27)
(14)
(14)

8 (36)
13 (59)
1 (5)
12 (55)
4 (18)
6 (27)
4
2
2
2
5
4
3

(18)
(9)
(9)
(9)
(23)
(18)
(14)

13 (59)
4 (18)
5 (23)
19 (86)
2 (9)
1 (5)
9
6
4
1
2

(41)
(27)
(18)
(5)
(9)

4 (18)
16 (73)
2 (9)
4 (18)
16 (73)
2 (9)

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289

viridans group streptococci (VGS) in 2 cases (9%), staphylococci in 2 cases (9%),

Streptococcus pneumoniae in 2 cases (9%), Candida spp in 2 cases (9%), and
Listeria monocytogenes, Bartonella quintana, Coxiella burnetii, Aspergillus
fumigatus, and Pseudallescheria boydii in one case each. This wide etiological
range reects several clinical and environmental conditions. In some cases
IE in HIV-1-infected patients was secondary to bacteria associated with
HIV-1 infection (Salmonella spp and S. pneumoniae). In other cases the
etiology was similar to the general population without HIV-1 infection
(VGS and enterococci). Other etiological agents (staphylococci) were secondary to episodes of catheter-related bacteremia (usually of nosocomial
origin) or from skin/soft tissue infections. Finally, unusual microorganisms
(fungi) were related to disseminated opportunistic infections with valve involvement in AIDS patients.
Surgery
Only four patients (18%) required surgery; none of them died. However,
non-IVDA HIV-infected patients are less likely to undergo surgery than
general population with IE [109].
Prognosis
Only four patients died (18%) during their hospital stay, a gure similar
to the mortality in-hospital ratio of the general population with IE
[108,109]. In this small series, HIV-1 infection alone and the HIV stage
appear to have little eect on the mortality from IE despite the fact that
more than half of cases had AIDS criteria.
In conclusion, prospective studies are needed with a larger cohort of nonIDVAs and HIV-positive IE patients to conrm and extend the understanding of this important topic.

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